IE861914L

IE861914L - Controlled release pharmaceutical

Info

Publication number: IE861914L
Application number: IE861914A
Authority: IE
Original assignee: Boehringer Ingelheim Int
Priority date: 1985-07-19
Filing date: 1986-07-18
Publication date: 1987-01-19
Also published as: NO862907D0; CA1289076C; PT83009A; IL79439A; PL260689A1; IE59024B1; FI862967A0; DE3683700D1; ES2001858A6; NO862907L; DK343586D0; FI88674B; AU6030486A; NO174086C; CS545286A2; JPS6270322A; NZ216897A; FI88674C; FI862967A; NO174086B

Abstract

The pharmaceutical composition is in the form of a carrier material with a pharmaceutical agent with controlled and delayed release of agent. The release of the agent can be adjusted by varying the particle size and the glass transition temperature.

Description

59024 - la- r v- The present invention relates to a controlled and delayed release pharmaceutical composition, and more particularly to a composition comprising a pharmaceutically active substance and at least 5 one carrier material allowing the controlled and delayed release of the active substance. The invention further relates to a process for preparing said pharmaceutical composition.

It is known to produce pharmaceutical coiapositions 10 in the form of capsulesr tablets and films which ensure a constant release of active substance and thus maintain a constant concentration of the active substance in the body™ In capsules and tablets the release of the active substance is usually 15 controlled by means of suitable coatings, e-g. as in the ease of film-coated tablets. Sustained-release forms may also be prepared from granulated mixtures of different carriers which release the plmnuaceuti-cally active substance at different rates*. A divisible 20 tablet with delayed release of the active substance is disclosed for example in DE-A-33 14 003; this tablet is prepared from an emulsion-polymerised polyacrylate, and the rate of release of active substance is controlled by means of the granule 25 size ajxd granule size distribution- ^ In systems for transdermal application, the release | of the active substance may be adjusted by means of a special membrane (see for example uS-A-3 731 683) or with the aid of adjuvants, for example aminesr 30 fats or higher alcohols. _ 2" - Howeverr the delayed release pharmaceutical compositions described in the prior art have not always proved entirely satisfactory in practice.. A reason for this is that tablets coated with a film alter 5 their active substance release characteristics after being divided up. A further reason is tfiat the possibility of controlling the release,of active substance by means of the granule size,. (/See DE-A-33™ 14 003)r is limited by the fact that the granule 10 size cannot be freely selected- As a result of technical problems such as inhomogeneity and the required minimum number of granules charged with active substance* the granule size in practice has an upper and a lower limitf with the result 15 that the optimum release rate for the active substance cannot be achieved in every case* Surprisingly, we have now found that, for a pharmaceutical composition consisting of an emulsion-polymerised carrier material, the rate of release can be adjusted 20 by simply varying the particle sise of the emulsion- polymerised polymer beads and by varying the glass temperature of the polymer.

The "particle sise" refers to the diameter of the particles of the polymeric carrier material after 25 they have been produced- Suitable particle sizes according to the invention are in the range of from SB" to 50a nm- The particle size (diameter) can be- adjusted as a function o-f the polymerisation conditions. A reduction in particle slize will JO lead to an increase in the rate of release.

Thus according to one aspect the present invention - 3 - provides a pharmaceutical preparation with a variable controlled and delayed release of active substance, containing a carrier material based on an emulsion polyrner, obtainable by suspending an emulsion polymer, which has been polymerised to a particle size of from 50 to 5 500 nm, having a glass temperature of between -20°C and +80°C, together with the pharmaceutical active substance, in a solvent, whilst the pharmaceutical active substance may also be dissolved in the solvent and 10 (a) pouring out the suspension which contains the active substance to form a film and, after evaporation of the solvent, optionally providing the film which contains the active substance with a vapour-impermeable backing layer and packaging said film or 15 (b) evaporating off the solvent, grinding the solid emulsion polymer which contains the active substance to a granule size of between 10 and 500 „um at a temperature below the glass transition temperature, processing it with conventional tablet-making excipients and compressing it to form tablets or packing it into capsules, 20 any reduction in the particle size resulting in an increase in the rate of release, and any rise in the glass transition temperature resulting in a reduction in the rate of release, excluding preparations consisting of an emulsion polyacrylate with a particle size of about 25 140 nm and a glass transition temperature of about 30°C. 30 ► 1 35 I - 4 - 5 One preferred active substance is clon.idine or or pharmacologically a physiologically^acceptable addition salt thereof* However other pharmaceutical^ active substances for which delayed and controlled release is desirable may of course be used* 10 Where the composition of the invention comprises the active substance and carrier in powdered (e.g„ granulated) form* for example where the composition is in tablet or capsule form?, then by a combination of varying the granule size* the particle size 15 and the glass temperature, it is possible to adjust the release characteristics for the active substance within a wide range.

In the case of pharmaceutical compositions in the form of transdermal films on the other hand* the rate of release may be adjusted by varying the particle size and the glass temperature and the thickness of the active substance containing layer. The layer thickness may conveniently be varied in the range of from 40 to 200 microns, preferably from 60 to 140 microns.

The glass temperature may be ad jus tea by altering the monomer composition frcm which the polymeric carrier material is formed. According to the invention the glass temperature is suitably in the- range 30 of -20 °C to +80"Cr preferably from -20e to +40°C, more particularly from -10° to +3ttcC* Any increase in the glass temperature leads to a reduction in the rate of release. r 20 25 - 5 - For compositions comprising the carrier material and the active substance in powdered (i.e. granulated) form, the granule size is ( conveniently in the range from 10 to 500 microns. In order to adjust the granule size, the emulsion-polymerised polymer having a selected 5 particle size may be dissolved together with the active substance in a suitable solvent, then poured out to form a film and the solvent is evaporated off. The film may then be ground to the desired granule size, possibly below its glass temperature, and screened if necessary. 10 Hence, according to a further aspect, the present invention provides a process for preparing a pharmaceutical preparation with variable controlled and delayed release of active substance, containing a carrier material based on an emulsion polymer, wherein an emulsion polymer, polymerised to a particle size of from 50 to 500 nm, having a 15 glass temperature of between ~20°C and +80°C, is suspended together with the pharmaceutical active substance in a solvent, whilst the pharmaceutical active substance may also be dissolved in the solvent, and 20 (a) the suspension which contains the active substance to form a film and, after evaporation of the solvent, the film containing the active substance is optionally provided with a vapour-impermeable backing layer and packaged or 25 (b) the solvent is evaporated off, the solid emulsion polymer which contains the active substance is ground to a granule size of between 10 and 500 at a temperature below the glass transition temperature, processed with conventional tablet-making excipients and compressed to form tablets or packed into capsules, 30 any reduction in the particle size resulting in an increase in the rate of release, and any rise in the glass transition temperature resulting in a reduction in the rate of release, whilst preparations consisting of an emulsion polyacrvlate with a particle size of about 140 nm and 35 with a glass transition temperature of about 30°C are excluded. - 6 - In the process of the inventions the granulate is preferably obtained by granulation below the glass temperature and suitably., optionally together with a pharmaceutical excipient or diluent, is compressed into tablets or filled into capsules.

The carrier material may consist of polymers or copolymers which can be produced by emulsion polymeri-10 sationr such as polyvinylchloride, poly lac tides, polystyrene, polyvinylacetate, polybutadiene, polyacryl-onitrile, polyvinylesters, polyvinylethers and the copolymers thereof- Emuls ion-polymerised copolymers of methyl and/or ethyl esters of acrylic and methacrylic 15 acid are preferred- The molecular weight of the emulsion polymers is conveniently in the range of A 7 from 10" to 10 » In its production, the carrier material may be recovered in solid form, for example by freeze-drying; the polymer particles then retain 20 their shape and size.

The pharmaceutical composition according to the invention may be produced by dissolving or suspending an emulsion polymer of the desired particle size and glass temperature together with the- active substance 25 in as volatile a solvent as possible- Suitable solvents for the solution or suspension containing the active substance and emulsion polymer include those having a low evaporation point, e-g-low-boiling alcohols such as methanolr ethanol, 30 acetone, methylethylketone, halogenated hydrocarbons such as methylene chloride* methyl and ethyl acetate, methyl and ethyl acetoacetate t, ethers such as tetrahydrofuran and d'ioxan, dimethylsulphoxide, and lofe' boiling freons, and mixtures of two or more 35 of these solvents™ - 7 - The rate of release of the active substance may additionally be varied by means of adjuvants, i.e. substances which will influence diffusion- These so-called adjuvants include, for e3caraplet. polyvinyl-5 pyrrolidone? cellulose esters, amines? fats and higher alcohols. If desired? these substances may be added to the solution of active substance.

This solution may be further processed as follows: In order to prepare a pharmaceutical composition 10 containing the active substance in the form of a film for transdermal therapeutic applications- the solution obtained is poured out to form a film of a defined layer thickness the dimensions of which are such that after evaporation of the solvent the IS film conveniently has a layer thickness in the range of from 40 to 200 microns# preferably between 60 and 140 microns- The film may then be provided with a vapour-xmpermeable backing layer and optionally.. an adhesive layer and may then be packaged. 201 in order to produce a pharmaceutical composition cocrfcsining the active substance in powder form? the solvexrt of the solution described above, is eliminated, optionally (e„g„ in the case of pharmaceutical compositions susceptible to moisture or 25 oxidation) under an inert gas* and the residue obtained is grotxn-d up to the ©©sired granule size of from 10 to S&© microns, preferably at a temperature below its glass temperature« If necessary, grinding may also be carried' oat in the presence of a filler, 30 e..g- an inert excipient, carrier or diluent such as lactose*, magnesium stearate, finely divided silica or similar finely divided lubricants- The mass ratio of active substance-containing emulsion polymer to finely divided filler may vary within wide limits - 8 - and conveniently ranges from about 10si to 1:4.

Further processing to form tablets or capsules may be carried out by known methods,, optionally using conventional excipients such as binders, inert fillers, 5 lubricants and disintegrants.

A preferred embodiment of the composition of the invention is in the form of a divisible tablet, since the composition according to the invention retains its advantageous properties even when frag-10 mented. When producing films for transdermal application, the rate of release for a given film thickness and quantity of pharmaceutical substance incorporated may be adjusted by varying the particle size and the glass temperature of the carrier material. 15 It is known that the rate of release increases substantially when the load on the carrier material is increased r with the result that sustained release of the active substance can no longer be guaranteed.

This could be compensated by increasing the granule 20 size, but there would then be a risk that the minimum number of loaded granules in a tablet would fall below the critical number of 400 (below which homogeneous distribution of the pharmaceutical active substance from tablet to tablet is no longer guaranteed). 25 According to the invention, the problem can be solved by selecting a higher glass temperature for the emulsion-polymerised carrier material and a larger particle size, whilst the granule size may be kept substantially constant - This makes it possible 30 to load the carrier material with a substantially greater quantity of pharmaceutical substance in J the case of tablets,, capsules or films. with the use of the invention, it is also possible to achieve more favourable ratios of pharmaceutical^ . 9 - active substance to carrier and hence to extend the sustained-release principle to pharmaceutically active substances administered in higher doses since the rate of release can be adjusted within 5 a wide range even with higher loads of active substance by means of the parameters of particle size? granule size and glass temperature described above.

Generally,, the compositions according to the invention preferably contain from 0.1 to 30% by weight, more 10 preferably from 1 to 10% by weight of active substance..

The following Examples are intended to illustrate the invention in a non-limiting manner (unless otherwise stated, all ratios and percentages are by weight)-The release characteristics of compositions according 15 to the invention are further illustrated in the accompanying drawings, in which:- Figure X is a graph showing as a function of time the percentage release of clonidine from compositons according to the invention in the form of films 20 for transdermal appliction« and Figure IT is a graph shoeing as a function of time the percentage release of Hxepexol from compos i tons according to the invention in the form of tablets.

V- - to - Examples A) Films; Example 1 The emulsion-polymerised polyacrylates listed in Table 1 are processed to form transdermal films and tested for their rates of release.

Table Is Emulsion-polymerised polyacrylate Carrier Glass temperature Diameter of polyacrylate latex particles A B C „ 8 °c + 29 °C ~ 8aC 50 ~ 100 nm 50 - 100 nm 100 - 150 nm The polyacrylate latex particles are obtained by drying off the water from the relevant dispersion (carrier A is Eudragit E 30 D from R5hm GmbH, Darmstadt, carriers B and C are of the same polymer material but differ in particle diameter and in glass temperature). 21.3 g of the dried polyacrylate are dissolved together with 1.6 g of clonidine in 142 g of acetone and poured onto a flat surface to form a film. The layer thickness after evaporation of the solvent is 80 microns. The rate of release was determined in the presence of an aqueous medium* pH 7f at 37®C, and the release analysis was performed using HPLC.

The diffusion coefficients obtained for the three different types of polyacrylate latex are listed in Table II: - 11 - Table II Carrie Diffusion coefficient D [cm2/dayj V 5 C B 5.5%10"6 4,4xlCTS 1.4xl0~6 Fig» I of the accompanying drawings shows the rates of release for the three physically different polyacrylate carrier materials A, B and C- As is clear 10 from the curves, the release characteristics may be influenced both by the particle size and by the glass temperature of the polyacrylate latices.

I- - 12 - Example 2: The emulsion-polymerised copolymers of vinyl chloride and acrylic acid ester listed in Table III are processed to form transdermal films and tested for their rate of release*.

Table in Carrier G H 10 Solid content of polymers in 44.6 % 44.7 % the dispersion Film forming temperature ( Glass temperature) 67®C 0°C Diameter of the polymer particles (particle size) 261 nm 262 nm The two carrier materials G and H {VP, 381 A and VA 381 3) obtained by emulsion polymerisation differ in their glass temperature ana hence in. the softness 20 of the polymer? the particle size however is similar for both products- The polymer is obtained by drying-fche aqueous dispersion, then it is dissolved- together wirh the phanaaceutically active substance ciotiMiae in methylene chloride and poured curt in known manner 25 to form films with a layer thickness of about 100 microns. The release of pharmaceutical^ active substance from a controlled percntcineotrs application 2 (CPA) film measuring 3 crm is determined in a USP tester and the content is analysed by HPLC. 30 The quantities of clonidine released fin percent) for various times is shown in Table IV. The rates of release decrease with increasing glass temperature, i.e., the harder the vinyl chrolide/acrylate latex the slower the release - - 13 - Table IV Quantity of clonidine release in % Time in days Carrier G Carrier H 5 V 0.33 26»3 47 a 2 66*8 70-2 50,9 67.7 73,0 74.4 1 4 5 10 Film thicknessr 100 microns? loading quantity 0-7 rag cionidine/cm^ B) Tablets; 15 Three different types of polyacrylate are each processed together with an active substance to form tablets and the release characteristics thereof are shown in Fig„ XI, The polymer carriers D and E are emulsion-polymerised poly-20 acrylates (as with carriers B and C above, they are of the same polymer material as Eudraait E 3G D of Rfihm--GmbH), and polymer carrier F (Eudragit RS 100) is a bulk-polymerised polyacrylate also available from Bdhnt GmbH. The two carrier types E and F have approximately the 25 same glass temperature (Tg = 30°C), but are in physically different forms: E is a latex in bead form and F is in the form of polymer coils. The glass temperature of polyacrylate carrier D4. also a latex in bead form,, is Tg = -80C. The glass temperature may be 30 adjusted by varying the proportions of monomers making up the polymer, whilst the shape may be altered by varying the conditions of polymerisation. - 14 - Example 3 23-75 g of polymer carrier E are stirred with 400 ml of acetone in a suitable container until a clear solution is formed,,, then the- solution of active 5 substance consisting of 1,25 g of B-HT 933 base (Azepexolr Boehringer Ingelheim) in 100 ml of methanol Is added- The solvent is evaporated off from the resulting solution under a protective gas atmosphere (N2) and the remaining film charged with active 10 substance is cooled to about -40°C using dry ice and ground in batches together with lactose in a ratio of 9:1 in a mill with rotating bladesr with cooling. A free-flowing powder is obtained in which the polyacrylate loaded with active substance is 15 present in a logarithmically normal distribution of between 65 and 500 microns- The mixture obtained as described above is compressed in a further operation, by conventional methods, with conventional tablet-making excipients such 20 as lactose, corn starch, colloidal silica and/or magnesium stearate, to form tablets which contain a 5% charge of active substance based on the polymer carrier» (8-HT 933 is 2-amino-6-ethvl-4,5,7,8-tetrahydro-SH-oxazolo [5,4,-d] azepine). 25 Example 4 Analogously to Example 3P .95 g of polyacrylate carrier E? dissolved in 500 ml of acetone and 5.0 g of B-HT 933 base in 40 ml of methanol are processed to form a film, which is then ground up and compressed into 30 tablets- Compagvative Example 5 Analogously to Example 3, 95 g of polymer carrier F dissolved in 250 ml of dichloronte thane and 5,0 g - 15 of B-HT 933 base in 40 ml of methanol are processed to form a film which is then ground up and compressed into tablets.

The _in vitro release of the active substance from 5 the tablets ms tested at 37 °C in a USP XvTI tester, using water at pH 7 as the receptor medium. Analysis was performed by HPLC. as is clear from Fig. II, the active substance has been almost totally released from the bulk polymerised 10 polyacrylate after only 2 hoursr whereas in the case of an emulsion-polymerised polyacrylate any desired release profile* e.g. fc^ 19%„ 60% release of pharmaceutically active substance, may be achieved by selection of the glass temperature. 15 I.

Claims

- 16 - .CLAIMS

1. Pharmaceutical preparation with a variable controlled and delayed release of active substance, containing a carrier material 5 based on an emulsion polymer, obtainable by suspending an emulsion polymer, which has been polymerised to a particle size of from 50 to 500 nm, having a glass temperature of between ~20°C and +80°C, together with the pharmaceutical active substance, in a solvent, whilst the pharmaceutical active substance may also be dissolved in 10 the solvent and (a) pouring out the suspension which contains the active substance to form a film and, after evaporation of the solvent, optionally providing the film which contains the active substance with a 15 vapour-impermeable backing layer and packaging said film or (b) evaporating off the solvent, grinding the solid emulsion polymer which contains the active substance to a granule size of between 10 and 500 ^m at a temperature below the glass transition temperature, 20 processing it with conventional tablet-making excipients and compressing it to form tablets or packing it into capsules, any reduction in the particle size resulting in an increase in the rate of release, and any rise in the glass transition temperature 25 resulting in a reduction in the rate of release, excluding preparations consisting of an emulsion polyacrylate with a particle size of about 140 nm and a glass transition temperature of about 30°C. 30

2. Pharmaceutical preparation as claimed in claim 1, wherein the emulsion polymer has a glass temperature of between -10 and +30°C.

3. Pharmaceutical preparation in the form of a tablet or capsule as claimed in claim 1 or 2, wherein the carrier material containing the 35 pharmaceutical active substance has a granule size of from 10 to 500 microns. <3 - 17 ~

4. Pharmaceutical preparation in the form of a film as claimed in claim 1 or 2, therein the film has a layer thickness of between 40 and 200 microns, preferably from 60 to 140 microns.

5. 5. Pharmaceutical preparation as claimed in claim 4, wherein the polymer consists of an emulsion-polymerised copolymer of methyl V and/or ethyl esters of acrylic and roethacrylic acid.

6. Pharmaceutical preparation as claimed in one of claims 1 to 5, 10 wherein it contains between 0.1 and 30 wt.% of active substance.

7. Pharmaceutical preparation according to claim 6, wherein the active substance is clonidine or a pharmacologically acceptable acid addition salt thereof. 15

8. Pharmaceutical preparation in the form of a tablet according to claim 1, 2, 3, 4 and/or 6, wherein the active substance is clonidine or a pharmacologically acceptable acid addition salt thereof. 20

9. Process for preparing a pharmaceutical preparation with variable controlled and delayed release of active substance, containing a carrier material based on an emulsion polymer, wherein an emulsion polymer, polymerised to a particle size of from 50 to 500 nm, having a glass temperature of between ~20°C and +80°C, is suspended 25 together with the pharmaceutical active substance in a solvent, whilst the pharmaceutical active substance may also be dissolved in the solvent, and (a) the suspension which contains the active substance to form a 30 film and, after evaporation of the solvent, the film containing the active substance is optionally provided with a vapour-impermeable backing layer and packaged or 35 (b) the solvent is evaporated off, the solid emulsion polymer which contains the active substance is ground to a granule size of between - 18 - 10 and 500 ^ra at a temperature below the glass transition temperaturee processed with conventional tablet-making excipients and compressed to form tablets or packed into capsules, 5 any reduction in the particle size resulting in an increase in the rate of release, and any rise in the glass transition temperature resulting in a reduction in the rate of release, whilst preparations consisting of an emulsion polyacrylate with a particle size of about 140 nm and with a glass transition temperature of about 30°C are 10 excluded.

10. Controlled and delayed release pharmaceutical compositions as defined in Claim 1 substantially as herein disclosed in any one of Examples 1 to 4. 15 Dated this 18th day of July, 1986. BY: T0MKINS & CO., Applicants' Agents, 20 (Signed) 5, Dartmouth Roade DUBLIN 6. 25 30 35 111 1R